PROJECT SUMMARY Cardiovascular disease is the leading cause of death in the United States. Prevention efforts can be costly or carry potential side effects and therefore are often directed based on predicted risk. However, there are major gaps in our ability to predict who will develop overt coronary heart disease or antecedent atherosclerotic and cardiometabolic disease. The health of millions of Americans is potentially affected, as lifesaving therapeutics are withheld unnecessarily or unneeded medications prescribed. Accurately predicting coronary heart disease risk is an especially vexing problem in young adults in whom low short-term risks often belie elevated lifetime hazards. Better biomarkers of risk are needed for the development of personalized cardiovascular disease prevention approaches. Recognition of the role of the epigenome in chronic disease has opened new avenues for clinical biomarker discovery. Methylation of cytosine-phosphate dinucleotides, one of the most well studied and characterized epigenetic modifications, influences gene expression without changing the underlying genetic sequence. DNA methylation reflects at the molecular level a wide range of environmental and genetic factors that may have been shaped by intergenerational and lifetime influences. The ability to study DNA methylation as a biomarker was made possible only recently by high throughput assays on thousands of individuals from deeply phenotyped disease cohorts. The proposed project will utilize rigorous evaluation methods to determine the clinical validity of DNA methylation biomarkers to predict coronary heart disease, subclinical atherosclerosis, and cardiometabolic disease in the Framingham Heart Study. In an independent pediatric cohort, the clinical utility will be examined in the context of evaluating how lifestyle interventions modify epigenetic-predicted risk and whether DNA methylation biomarkers can predict who will respond to a lifestyle modification intervention. DNA methylation biomarkers will be evaluated using a lifecourse approach ranging from adolescents to older adults. The candidate for this career development award, Dr. Michael Mendelson, is a pediatric cardiologist with a Masters of Science degree in epidemiology and experience in cardiovascular disease epidemiology and population-based DNA methylation studies. In order to achieve scientific independence for the candidate, a comprehensive career development program has been developed to gain additional needed training in the areas of: 1) statistical coding and bioinformatics, 2) advanced risk prediction methods, and 3) state-of-the-art epigenetic mechanisms. This will be accomplished through coursework and seminars, under the mentorship of leaders in the field of genetic epidemiology (Joel Hirschhorn), cardiovascular disease epidemiology (Daniel Levy), and risk prediction (Ralph D'Agostino Sr.), with regular progress monitoring by an advisory committee.